The steps which lead to development of primary hepatocellular carcinoma (PHC) remain enigmatic, although several possible etiologic agents have been identified. The major goal of this proposal is to identify the common changes that lead to hepatocarcinogenesis of different etiologies, and to determine whether or not specific mechanisms underlie the induction of these changes. We will characterized these changes on a chromosomal and molecular level by direct investigation of tumor and normal cells from the same patient and by preparing hepatoma-derived cell lines and normal cells from the same patient and by preparing hepatoma- derived cell lines and normal fibroblasts from the same patient to provide unlimited quantities of material for assay. Our previous chromosome analyses pointed to consistent translocation and deletions of chromosome analyses pointed to consistent translocation and deletions of chromosome 1 in hepatoma-derived cells. Comparison of DNA obtained form tumor cells and normal cells from the same patient using probes form 1p revealed loss of heterozygosity in this area of the genome in the tumor cells. On the basis of these preliminary data, we hypothesized that the loss of a tumor suppressor gene is a likely initiating step in PHC development. Our proposal is aimed at establishing evidence for a chromosome 1 encoded change common to PHCs of multiple origins. We will then define how such a change may be initiated. To accomplish this, we will extend our study of loss of heterozygosity of 1p-encoded genes to more patients with PHC of different etiologies and expand our panel of 1p-derived probes. We will also attempt to detect genetic instability and the mutagenic role of hepatitis B virus (HBV) in PHC development.